The existence of a specific GHB receptor was predicted by observing the action of GHB and related compounds that primarily act on the GABAB receptor, but also exhibit a range of effects which were found not to be produced by GABAB activity, and so were suspected of being produced by a novel and at the time unidentified receptor target. Following the discovery of the "orphan" G-protein coupled receptor GPR172A, it was subsequently found to be the GHB receptor whose existence had been previously predicted. The rat GHB receptor was first cloned and characterised in 2003 followed by the human receptor in 2007.
The function of the GHB receptor appears to be quite different from that of the GABAB receptor. It shares no sequence homology with GABAB, and administration of mixed GHB/GABAB receptor agonists along with a selective GABAB antagonist or selective agonists for the GHB receptor which are not agonists at GABAB, do not produce a sedative effect, instead causing a stimulant effect followed by convulsions at higher doses, thought to be mediated through increased Na+/K+ current and increased release of dopamine and glutamate.
^Andriamampandry C, Taleb O, Viry S et al. (September 2003). "Cloning and characterization of a rat brain receptor that binds the endogenous neuromodulator gamma-hydroxybutyrate (GHB)". FASEB J.17 (12): 1691–3. doi:10.1096/fj.02-0846fje. PMID12958178.CS1 maint: Explicit use of et al. (link)
^Andriamampandry C, Taleb O, Kemmel V, Humbert JP, Aunis D, Maitre M (March 2007). "Cloning and functional characterization of a gamma-hydroxybutyrate receptor identified in the human brain". FASEB J.21 (3): 885–95. doi:10.1096/fj.06-6509com. PMID17197387.
^Castelli MP, Ferraro L, Mocci I et al. (November 2003). "Selective gamma-hydroxybutyric acid receptor ligands increase extracellular glutamate in the hippocampus, but fail to activate G protein and to produce the sedative/hypnotic effect of gamma-hydroxybutyric acid". J. Neurochem.87 (3): 722–32. doi:10.1046/j.1471-4159.2003.02037.x. PMID14535954.CS1 maint: Explicit use of et al. (link)
^Castelli MP (November 2008). "Multi-faceted aspects of gamma-hydroxybutyric Acid: a neurotransmitter, therapeutic agent and drug of abuse". Mini Rev Med Chem8 (12): 1188–202. doi:10.2174/138955708786141025. PMID18855733.
^Høg S, Wellendorph P, Nielsen B et al. (2008). "Novel High-Affinity and Selective Biaromatic 4-Substituted gamma-Hydroxybutyric Acid (GHB) Analogues as GHB Ligands: Design, Synthesis, and Binding Studies". J. Med. Chem.51 (24): 8088–95. doi:10.1021/jm801112u. PMID19053823.CS1 maint: Explicit use of et al. (link)